Target regimen profiles for tuberculosis treatment

Abstract Simpler, shorter, safer and more effective treatments for tuberculosis that are easily accessible to all people with tuberculosis are desperately needed. In 2016, the World Health Organization (WHO) developed target regimen profiles for the treatment of tuberculosis to make drug developers aware of both the important features of treatment regimens, and patient and programmatic needs at the country level. In view of recent ground-breaking advances in tuberculosis treatment, WHO has revised and updated these regimen profiles. We used a similar process as for the 2016 profiles, including a baseline treatment landscape analysis, an initial stakeholder survey, modelling studies estimating the impact and cost-effectiveness of novel tuberculosis treatment regimens, and an extensive stakeholder consultation. We developed target regimen profiles for the treatment of rifampicin-susceptible and rifampicin-resistant tuberculosis, as well as a pan-tuberculosis regimen that would be appropriate for patients with any type of tuberculosis. We describe the revised target regimen profile characteristics, with specific minimal and optimal targets to be met, rationale and justification, and aspects relevant to all target regimen profiles (drug susceptibility testing, adherence and forgiveness, treatment strategies, post-tuberculosis lung disease, and cost and access considerations). We discuss the trade-offs of proposed characteristics for decision-making at developmental or operational levels. We expect that, following these target regimen profile revisions, tuberculosis treatment developers will produce regimens that are quality-assured, affordable and widely available, and that meet the needs of affected populations.


Introduction
Significant progress has been achieved over the last two decades in the development of tuberculosis treatment, with the discovery of new chemical entities and trials testing new combinations of drugs.2][3] With new chemical entities currently transitioning into clinical testing, the possibility of more efficacious, shorter and safer regimens for all forms of tuberculosis now appears to be achievable. 4he early 2000s brought the discovery of new chemical entities with new modes of action on tuberculosis bacilli, 5,6 such as the development of diarylquinolines and nitroimidazoles, and the repurposing of active compounds traditionally used against Gram-positive infections (oxazolidinones); 7 all these developments played a major role in advancing new treatment options for drug-resistant tuberculosis.In parallel, WHO proposed new approaches to shorten the lengthy development pathway, breaking away from the classical approach of Bull World Health Organ 2024;102:600-607| doi: http://dx.doi.org/10.2471/BLT.24.291881   Christian Lienhardt et al.Tuberculosis target regimen profiles first testing single new compounds and then identifying the most suitable drug combination. 8,9n 2017, WHO published Target regimen profiles for treatment of tuberculosis, promoting an end-to-end process integrating the development of new drugs within the development of new regimens, and defining specific requirements that new regimens should meet. 10n view of the ground-breaking progress in tuberculosis treatment over recent years, and the subsequent transformations in the recommended standards of care by WHO, it is necessary to revise and update these target regimen profiles.

Methods
The revision of the target regimen profiles for tuberculosis treatment by WHO followed similar methods to those established for initial regimen development in 2016.The WHO Global Tuberculosis Programme established a Scientific Target Regimen Profile Development Group that included leading scientists and experts, public health officials, regulators, donors, programme managers and representatives of civil society organizations.Our group served to support the entire development process by reviewing drafts at several stages, contributing to discussions during meetings and assisting with the writing process.
After a critical review of the 2016 document, our group retained the initial approach of classifying target regimen profiles for rifampicin-susceptible and rifampicin-resistant tuberculosis.Further, considering the possibility of developing a regimen composed of entirely new antituberculosis drugs for which minimal or no resistance would exist, we maintained the pan-tuberculosis profile.We conducted a stakeholder survey during May-July 2022 to assess the use of the 2016 target regimen profiles, evaluate the relevance of the proposed regimen characteristics, prioritize these characteristics and evaluate potential trade-offs.The WHO Global Tuberculosis Programme commissioned two complementary modelling studies to inform our discussion.The first study estimated the potential health impact of novel treatments on the outcome of cure, considering various regimen characteristics such as treatment efficacy, duration, ease of adherence and forgiveness.The second study estimated the price thresholds below which novel rifampicinsusceptible tuberculosis and rifampicinresistant tuberculosis regimens would be cost-neutral or cost-effective. 11he target regimen profiles proposed here aim to guide the development of new tuberculosis treatment regimens, considering end-user needs and real-world conditions.We established a list of 13 characteristics -eight of which are common to all target regimen profiles (target population; populations of special interest; drug-drug interaction and metabolism; forgiveness of the regimen; number of component drugs; formulation or dosage form, dosing frequency and route of administration; propensity to develop resistance; and stability or shelf life); and five of which are regimen-specific (indication and need for drug susceptibility testing; efficacy; duration; safety, monitoring and tolerability; and pill burden) 11 -and identified minimal and optimal targets for each.The expectation is that any regimen that is developed will meet most of the minimal requirements and as many of the optimal requirements as possible.
Based on this preliminary work, we developed an initial draft document that was shared with the group for revision and comments.We then divided into three subgroups who worked through virtual consultative meetings on each of the target regimen profiles, leading to a new version that was posted by WHO for public comment in February 2023.In March 2023, our group met to discuss the latest draft and reached full consensus on the contents of the document.

Target population
Regimens should be intended for all population groups, irrespective of age, site of disease, clinical severity and comorbidities.The regimens must have an acceptable safety profile, be well tolerated and efficacious in all these groups (including neonates, infants, children, women of reproductive age, and pregnant and lactating women), 12 as well as in those with comorbid conditions.Treatment developers should initiate paediatric studies as soon as a drug shows promising efficacy and safety in Phase 2 adult trials. 13

Populations of special interest
Human data indicate that the treatment does not cause any increased risk of structural abnormalities in the fetus, and the drugs are safe for women of childbearing potential, and pregnant and lactating women.The component drugs should be compatible with common forms of hormone-based birth control for women of reproductive age who do not wish to become pregnant.

Drug-drug interaction and metabolism
New chemical entities should have minimal or no drug-drug interaction with the other components of the regimen combination.For people living with human immunodeficiency virus undergoing antiretroviral therapy, drug-drug interaction studies should be initiated as soon as doses are known; ideally, no dose adjustments as a result of drug-drug interactions should be required. 14

Forgiveness of the regimen
Imperfect adherence increases the risk of unfavourable treatment outcomes. 15n this basis, forgiveness of a regimen, defined as "the degree to which regimen efficacy is unaffected by suboptimal adherence," 11 was introduced as a new regimen characteristic.Because it can be challenging to ensure full daily drug administration under programmatic conditions, highly forgiving regimens are desirable.

Number of component drugs
Regimens containing three to four drugs would provide the best balance to ensure high efficacy and minimize the risk of developing drug resistance.Further, limiting the number of component drugs in a regimen helps to minimize pill burden and safety risks, and facilitates drug coformulation.

Formulation
Formulation should be all-oral, with simple, age-or weight-based dose adjustment.Fixed-dose combination formulations as well as child-friendly formulations are strongly encouraged.Policy & practice targets, 16 have different pharmacokinetic-pharmacodynamic properties, be active and synergistic at the lesion site level, 17 and have half-lives that are well matched to reduce the risk of functional monotherapy.

Stability and shelf life
Ideally, all component drugs should be stable for at least 5 years in climate zones III and IV (i.e. 30 °C and 75% relative humidity).

Rifampicin-susceptible tuberculosis
Despite its wide availability, low cost and high efficacy, the current 6-month treatment of rifampicinsusceptible tuberculosis has several limitations, including adverse events, drug-drug interactions and adherence requirements.A 4-month regimen was recommended by WHO as non-inferior to the 6-month regimen in 2020, but its uptake remains limited because of its high cost, lack of a fixed-dose combination and concerns about the use of a fluoroquinolone. 11

Indication and drug susceptibility testing
The rifampicin-susceptible tuberculosis regimen is indicated for patients with active tuberculosis disease caused by rifampicin-susceptible Mycobacterium tuberculosis strains, including forms with monoresistance to isoniazid, pyrazinamide and ethambutol (the other drugs included in the current 6-month treatment regimen).

Efficacy and duration
The current 6-month regimen of isoniazid, rifampicin, pyrazinamide and ethambutol has 90-95% efficacy under trial conditions. 18The efficacy and duration targets aim to improve on the current 4-month WHO-recommended treatment (comprising the drugs isoniazid, rifapentine and moxifloxacin, with the addition of pyrazinamide in the first 2 months).However, the optimal target is based on the possible development of a 2-month regimen, as recently shown within the context of a sustained treatment monitoring strategy trial. 19

Safety and tolerability
Although serious adverse events with the current standards of care are uncom-mon, important tolerability issues affect adherence and, as a result, effectiveness.The safety and tolerability of a new rifampicin-susceptible regimen should be at least equal to, and ideally better than, the current standards of care.Demands for active clinical and laboratory monitoring for drug toxicity should be minimized.

Pill burden
A regimen would ideally comprise just one pill per day; minimally, the pill burden should not be greater than for the 6-month regimen of isoniazid, rifampicin, pyrazinamide and ethambutol.

Rifampicin-resistant tuberculosis
In 2020, the global success rate for treatment of multidrug-resistant (MDR) tuberculosis (i.e.tuberculosis that is resistant to both rifampicin and isoniazid) was 60%. 20Treatment typically lasted 9-18 months and included a large number of drugs, resulting in high pill burden and frequent side-effects that often led to discontinuation of treatment.The recently recommended bedaquiline, pretomanid, linezolid and moxifloxacin regimen promises improvements; however, the safety profile is still suboptimal 21 and careful implementation will be important to prevent emergence of resistance to component drugs. 22

Indication and drug susceptibility testing
Under the minimal requirement, a rifampicin-resistant tuberculosis regimen is indicated for patients with active tuberculosis disease caused by rifampicin-resistant strains, with or without isoniazid resistance.Under the optimal requirement, the regimen is indicated for patients with active tuberculosis caused by either MDR tuberculosis, pre-extensively drugresistant tuberculosis (caused by strains that are both MDR-and fluoroquinolone-resistant) or extensively drug-resistant tuberculosis (caused by strains resistant to any fluoroquinolones and at least one other Group A drug). 23Drug susceptibility testing is essential before initiation of treatment to establish the resistance pattern of the strains and guide the composition of the regimen.Under the optimal requirement, susceptibility to the drugs in the regimen should be established through appropriate phenotypic or genotypic testing.In all cases, usage should be consistent with principles of good antibiotic stewardship. 24

Efficacy and duration
The 2022 WHO tuberculosis treatment guideline update recommends the 6-month bedaquiline, pretomanid, linezolid and moxifloxacin regimen for most adult patients with tuberculosis that is MDR or rifampicin resistant.This regimen is approximately 90% efficacious. 25Consequently, a new rifampicinresistant-tuberculosis regimen should, at a minimum, have an efficacy at least as good as this newly recommended regimen and a similar duration; optimally, it should have a better efficacy and shorter duration than the 2022 regimen.

Safety and tolerability
The minimum and optimum targets are identical: it is suggested that the incidence and severity of adverse events with any new MDR-tuberculosis regimen should be lower than for the current regimens to guarantee best tolerability, acceptability and effectiveness under programmatic conditions.In the pivotal trial of the bedaquiline, pretomanid, linezolid and moxifloxacin regimen, adverse events of at least grade 3 occurring during treatment or up to 30 days after treatment were observed in 18% of patients (mainly hepatic, pancreatic or haematological disorders). 3The proportion of patients discontinuing this regimen because of non-tolerability was 5%. 3

Pill burden
A regimen would ideally comprise not more than four to five pills per day; minimally, the pill burden should not be greater than five to seven pills per day.

Indication and drug susceptibility testing
A regimen containing fully novel compounds with no cross-resistance could be used as a first-line tuberculosis regimen in individuals with tuberculosis disease without prior knowledge of the patient's drug resistance profile.This approach would allow treatment to begin without delay while drug susceptibility testing is sought.Such a pan-tuberculosis regimen would be particularly useful in areas with a high prevalence of drug resistance and low availability of, or low access to, rapid drug susceptibility testing; current practice in such areas means that patients may be treated with inappropriate regimens and may con-

Efficacy and duration
Considering that a pan-tuberculosis regimen would be used to treat both rifampicin-susceptible and rifampicinresistant tuberculosis, efficacy should be at least as good as the current rifampicin-susceptible tuberculosis regimen, with a duration of no more than 3-4 months.Optimally, efficacy should be better than the current regimen and, based on recent results indicating that a carefully applied monitoring strategy can make it possible to provide a cure with a 2-month regimen, 19 duration should be equal to, or less than, 2 months.

Safety and tolerability
In line with the recommendations for the rifampicin-susceptible and rifampicin-resistant tuberculosis regimens, and considering that the pan-tuberculosis regimen will be provided to a larger proportion of patients with rifampicinsusceptible than rifampicin-resistant tuberculosis, it is expected that the incidence and severity of adverse events should be lower and tolerability better than for the rifampicin-susceptible tuberculosis regimen, as both a minimal and an optimal target.

Pill burden
A regimen would ideally comprise just one pill per day; minimally, the pill burden should not be greater than for the 6-month regimen of isoniazid, rifampicin, pyrazinamide and ethambutol.

Cross-cutting aspects
We discuss several key aspects that are relevant across all three regimens: drug susceptibility testing; adherence and forgiveness; treatment strategies; posttuberculosis lung disease; and cost and access considerations.

Drug susceptibility testing
Phenotypic or genotypic tests should be available at time of regimen introduction for both individual patient care and population-level surveillance.Drug developers need to support this by establishing minimum inhibitory concentration distributions and drug susceptibility testing interpretative criteria.To allow an understanding of resistance mechanisms, the identification of target genes and the development of rapid drug susceptibility testing, drug developers must also provide access to resistant mutants and drug compounds with detailed accompanying information (including stability, storage and solubility).

Adherence and forgiveness
Poor adherence affects treatment outcomes and increases the risk of developing resistance, although uncertainty remains with regards to the magnitude of this effect. 26A meta-analysis of trial participants receiving isoniazid, rifampicin, pyrazinamide and ethambutol suggested that those who missed 10% or more of treatment doses had a 5.9-fold greater risk of unfavourable treatment outcome. 15This outcome suggests that imperfect adherence has a major impact on treatment outcomes and that, with the current dosing, such a regimen is unforgiving.However, studies to date present conflicting findings, showing considerable uncertainty about the degree to which improving adherence may enhance treatment outcomes. 27High levels of poor adherence have been observed outside of well-controlled clinical trials; 27 developing more forgiving regimens that retain high proportions of patients cured under such circumstances -and are therefore effective and not just efficacious -is an important priority.

Treatment strategies
Beyond the specific characteristics of treatment regimens, novel treatment strategies such as stratified medicine approaches may be implemented to maximize the benefits and minimize the harms of treatment.Re-analyses of clinical trial data suggest that a difficult-to-treat subset of patients with rifampicin-susceptible tuberculosis may require longer than 6 months of the regimen to reach target cure, while most patients could be successfully treated in 4 months or less. 15,28Further research is needed to investigate the use and applicability of stratified approaches for tuberculosis treatment under programmatic conditions.

Post-tuberculosis lung disease
There is increasing recognition that pulmonary tuberculosis (both rifampicin-susceptible and rifampicin-resistant) may result in clinically significant lung injury and functional impairment, termed post-tuberculosis lung disease, even in patients whose treatment is otherwise successful.Developers are encouraged to incorporate evaluation of lung injury and functional impairment into trial designs.As our understanding of post-tuberculosis lung disease grows, developers may anticipate the inclusion of a new characteristic in future target regimen profiles: the ability to limit lung injury and functional impairment, and therefore the emergence of posttuberculosis lung disease.

Cost and access considerations
Given the significant role of public financing for tuberculosis research and development, new products should be appropriately priced to reflect overall investments by global public and publicprivate actors, including governments, philanthropists, and other research and product sponsors.Any resulting product should deliver a public return on investment, and be linked to public health-driven priorities and application of the core principles of affordability, effectiveness, efficiency and equity.Developers should aim for new tuberculosis regimens that are cost-neutral, if not cost-saving, to health systems, considering both drug and non-drug costs.Our modelling analysis suggests that costlier regimens can still be cost-neutral if optimal regimen targets are met, as this would reduce non-drug costs (e.g.treatment monitoring visits or patient adherence support). 11There should be collective efforts to ensure accelerated development, commercialization and scale-up of affordable regimens satisfying the criteria laid out in these target regimen profiles.

Discussion
The

Policy & practice
including the clinical perspective (where probability of cure is a priority); the economic perspective (relating to the costs to health systems and patients); the patients' perspective (drawing on experiences of tuberculosis survivors); and the expected long-term impact at the population level.
We undertook a modelling analysis to estimate the impact on health outcomes and costs of improving various regimen characteristics. 11In this analysis, ease of adherence (defined as the proportion of prescribed doses that patients take effectively while still on treatment) had the greatest influence on proportion of patients cured.For regimens meeting all the minimal characteristics of their respective target regimen profiles, complete adherence (as might be achieved via a long-acting injectable) increased the percentage of patients cured from 83% to 93% for rifampicin-susceptible tuberculosis, and from 74% to 85% for rifampicinresistant tuberculosis. 11Improving the efficacy of the regimen was the next most influential characteristic, especially for rifampicin-resistant tuberculosis.Of note, shortening treatment duration had a smaller effect on cure than other modelled characteristics, but had the greatest influence on reducing costs. 11his finding aligns with observations from the stakeholders' survey, in which respondents expressed that regimens should primarily demonstrate strong efficacy (even at the expense of longer duration), followed by safety, treatment duration, frequency of intake and pill burden.
Drug developers should therefore consider the capacity of their proposed regimen under development to be best used in programmatic conditions.Indeed, beyond the intrinsic pharmacological and antibacterial characteristics of new regimens, their clinical and public health impact will also depend on operational and epidemiological factors that affect regimen use (e.g. the ability to access, afford and distribute new regimens; the availability of clear guidance for clinicians; the background prevalence of antimicrobial resistance; and the development of resistance to new drugs). 29For these reasons, the respective characteristics to be considered at the developmental stage should not be dissociated from the factors to be considered at implementation stage; we need effective regimens that are accessible, affordable and work for people and programmes, not just efficacious regimens that work well in clinical trials.To simplify regimen development, and ensure that products are fit for purpose and can meet the needs of affected communities (particularly in low-resource areas), developers should therefore (i) work within open collaborative models for tuberculosis research and development to enable early sharing of research knowledge; and (ii) consult affected communities to ensure that needs and priorities of patients are driving the final product and use-case.
This target regimen profile update also highlights the deleterious impact of drug resistance.Developers should work in partnership with reference laboratories and diagnostic manufactur-ers to identify protocols and standards for phenotypic and genotypic tests, providing the necessary tools (compounds, mutants if available, information on drug resistance mechanisms) in parallel with drug development.A pan-tuberculosis regimen could facilitate implementation of tuberculosis treatment, but should be considered as a better first-line regimen for all and not a drug-susceptibility-testing-free regimen.The 2016 target regimen profile encouraged a shift in focus from drug to regimen development; the 2023 profiles draw awareness to considering not just regimens but treatment strategies to optimize care of patients.
In conclusion, the revised target regimen profiles described here represent an important step towards the development of new regimens for the treatment of all forms of tuberculosis.These profiles are expected to serve as a reference for research consortia involving drug developers, academics, public health institutions, nongovernmental organizations and civil society organization representatives, so that better treatment of all forms of tuberculosis is available to achieve the targets of the WHO end tuberculosis strategy. 30